Transcript SHOCK - Division of Critical Care

Shock
Division of Critical Care Medicine
University of Alberta
OUTLINE
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Classification
Common Pathways for Shock
Initial Management
Characterization
Mechanism of Inotropy
Catecholamines
What’s Next?
SHOCK
A syndrome characterized
by inadequate cellular
oxygen delivery with
widespread organ damage
and dysfunction.
CLASSIFICATION
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HYPODYNAMIC
Cardiogenic
 Hypovolemic
 Obstructive
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HYPERDYNAMIC
 Distributive
CARDIOGENIC SHOCK
LV infarction
 RV infarction
 Valvular dysfunction
 Cardiomyopathy
 Arrhythmias
 Dynamic outflow obstruction
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HYPOVOLEMIC
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May occur with fluid loss from any
compartment.
Patients with diastolic dysfunction have
marked preload dependence with
extreme sensitivity to volume status.
Ischemic and reperfusion injury cause
endothelial dysfunction and refractory
shock.
OBSTRUCTIVE CAUSES
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Pulmonary embolism
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Cardiac tamponade
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Aortic dissection
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Tension pneumothorax
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Auto PEEP
DISTRIBUTIVE SHOCK
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Sepsis
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Anaphylaxis
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Neurogenic
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Adrenal insufficiency
WHATEVER THE ORIGINAL MODE OF
SHOCK, DECOMPENSATION OCCURS VIA
COMMON PATHWAYS
Hypovolemia
 Vasodilatation
 Myocardial depression
 Mediator cascade activations
 Microcirculatory dysfunction
 Impaired mitochondrial
respiration
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HYPOVOLEMIA
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Endothelial injury results in increased
capillary permeability and diminished
reflectance to albumin.
Dilation of capacitance vessels leads to
venous pooling and reduction in mean
systemic pressure.
Translocation of fluid to body cavities and
the GI tract can occur very quickly.
VASODILATION
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NO release after induction of iNOS.
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Endothelial membrane hyperpolarization
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Decreased adrenoreceptor sensitivity
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? norepinephrine inactivation by
peroxynitrite
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Vasopressin deficiency
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Relative cortisol deficiency
Vessel constriction dependent on ingress
of Ca++ through voltage dependent
channels.
Activation of ATP sensitive K+ channels allows
membrane hyperpolarization and inactivates Ca++
channels.
MYOCARDIAL DEPRESSION
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Biventricular dilation and hypocontractility typical of
septic shock.
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EF usually 30 - 40 % but may be much lower.
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Cytokine and NO mediated.
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Troponin release marker for depression.
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Degree of dilation associated with survival (more
dilation, better prognosis).
MEDIATOR ACTIVATION
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Infection directly activates innate immune
mechanisms via TLRs.
Other shock states indirectly do so following
ischemia / reperfusion injury or after bacterial
translocation from the gut.
Activation of nuclear factor-b results in cytokine
transcription.
Elaboration of TNF and Interleukin 1 central to
development of SIRS.
MICROCIRCULATORY
DYSFUNCTION
VOLUNTEER
SEPSIS
MICROCIRCULATORY
DYSFUNCTION
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Endothelial injury and loss of
autoregulation
Leukocyte rolling and adherence
DIC with fibrin strands and micro
thrombi
Tissue edema
Decreased capillary density and high
flow shunts
Impaired oxygen diffusion
MITOCHONDRIAL FAILURE
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Electron transport chain inhibited by NO and its
metabolite peroxynitrite.
Evidence of actual mitochondrial injury.
Responsible for declining VO2 in setting of
increased DO2.
Failure of cellular energetics may be key factor
in organ dysfunction.
INITIAL MANAGEMENT
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Usually necessary to initiate
resuscitation prior to a full assessment.
Don’t forget the ABCs.
Responses to resuscitative maneuvers
give clues to cause of shock.
RESPIRATORY
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Encephalopathy may develop early requiring the
airway to be protected.
Hypoxemia and increased work of breathing may
develop insidiously.
Early intubation and ventilation will decrease O2
requirements and improve O2 transport.
Adopt a “lung protective” strategy early in
course of acute lung injury.
VENOUS ACCESS
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Large bore peripheral IVs more effective for
giving fluids rapidly.
Large caliber dual lumen dialysis catheters most
effective in setting of exsanguinating
hemorrhage.
Central lines should preferably be placed above
diaphragm to allow monitoring of CVP and SvO2.
Beware femoral catheter sheaths which are
easily displaced extravascularly as edema
progresses.
BP MEASUREMENT
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Sphygmomanometry may be inaccurate in the
vasodilated patient and difficult in the
constricted.
Radial arterial lines may read significantly below
a central arterial pressure with vasoconstriction.
Femoral arterial lines most accurate in phase of
active resuscitation but consider early relocation.
With severe atherosclerotic disease or dissection
it may be impossible to measure an accurate BP.
CORRECTION OF HYPOTENSION
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Myocardial ischemia may occur at low pressures
even with normal coronary anatomy.
Potential for cerebral ischemia and watershed
infarcts.
Initial measure will usually be administration of
volume challenge.
It may be necessary to use vasopressors in a
setting of recognized hypovolemia or
hemorrhage to correct profound hypotension.
ASSESSMENT GOALS
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Establish cause to allow definitive therapy.
Quantitate physiological derangements.
 Severity of myocardial depression, volume
contraction and vasodilatation vary widely in
septic patients.
Document adequacy of resuscitation
 Restoration of normal vital signs often not
consistent with normal hemodynamics or
microcirculatory function.
CHARACTERIZATION
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IS CARDIAC OUTPUT HIGH OR LOW?
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IS THE HEART FULL?
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WHAT IS THE RESPONSE TO VOLUME?
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WHAT IS THE RESPONSE TO INOTROPE?
CLINICAL EXAM
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Peripheries cool and clammy or well
perfused?
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Pulses bounding or low volume ?
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Jugular veins flat or distended ?
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What is the response to leg raising ?
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Is there evidence of organ hypoperfusion ?
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oliguria
obtundation
HEMODYNAMIC MONITORING
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Increases ability to characterize shock with
knowledge of C.I. and S.V.R.I.
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Allows measurement of oxygen delivery and
consumption.
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However, filling pressures a poor surrogate for
estimation of ventricular filling or preload.
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Useful monitoring tool in some circumstances
but generally not shown to be of benefit.
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? inherently misleading
? inadequate interpretation
? ineffective interventions
ECHOCARDIOGRAPHY
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Gives definitive diagnostic information in many
circumstances.
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Much more reliable guide to the adequacy of
ventricular filling.
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Should always be employed when invasive
hemodynamic monitoring is being considered.
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Increasing availability of bedside technology.
MIXED VENOUS OXIMETRY
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As oxygen extraction rises relative to DO2, SvO2
falls.
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Low SvO2 correlates with inadequate global DO2
and tissue hypoxia.
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Normal SvO2 does not exclude areas of regional
ischemia.
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Measurements by intermittent sampling or
reflectance oximetry.
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Use as a guide for response to therapy.
ARTERIAL LACTATE
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Multiple causes of increased lactate in
sepsis.
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Tissue ischemia
Hepatic hypoperfusion or failure
Increased alanine metabolism “Cori cycle”
Inhibition of pyruvate dehydrogenase
Elevation of lactate > 2mmol/L a marker
for increased mortality and its failure to
fall with Rx more strongly so.
GASTRIC TONOMETRY
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Saline filled gastric balloon equilibrates with
gastric mucosal pCO2.
Impaired tissue perfusion leads to accumulation
of tissue pCO2 and increasing gap between
tissue and arterial pCO2.
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Correlates with other evidence for tissue hypoxia
and with outcome.
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Expensive and unwieldy.
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Limited improvement in discrimination compared
to lactate levels.
RESEARCH TOOLS
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Direct measurement tissue pO2.
Near infrared spectroscopy.
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Luminescent oxygen probes
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Redox state of NADH
Microdialysis
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Redox state of cytochrome oxidase
tissue lactate
PET scanning
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ATP levels
MANAGEMENT GOALS
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Normalize vital signs.
Normalize global O2 transport.
Eliminate evidence of tissue dysoxia.
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Definitive Rx of cause:
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Source control and antibiotics in sepsis
Thrombolysis of PE
PCI in MI
Organ protective strategies
OPTIMIZE PRELOAD
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Fundamental to any resuscitation strategy
FLUID CHALLENGES MUST BE OF ADEQUATE
VOLUME , BE INFUSED RAPIDLY AND THE
EFFECTS OBSERVED IMMEDIATELY
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Monitoring of response to volume challenge
 Clinically
 Hemodynamic parameters
 Echocardiographically
CHOICE OF FLUID
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No evidence of increased efficacy of albumin
compared to crystalloid solutions.
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Limited trials of non albumin colloids (i.e.
Pentaspan).
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Large volumes of N/S contribute to metabolic
acidosis.
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Pentaspan contributes to coagulopathy in large
volumes or in already coagulopathic patients.
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Some evidence of improved efficacy with
hypertonic saline solutions.
? OPTIMAL HEMATCRIT
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Transfused blood recognized to be
immunosuppressive and to independently
contribute to mortality.
Limitation of oxygen carrying capacity of stored
RBCs due to low levels of 2,3 DPG.
In absence of myocardial ischemia a transfusion
trigger of < 7g/l improved or did not worsen
outcome.
In presence of lingering evidence of tissue
hypoxia transfusion to Hb 10 g/l should be
considered.
MECHANISMS OF
INOTROPY
DIFFERENTIAL
RESPONSIVENESS
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The effects of any vasoactive agent may be
quite different depending on numerous
premorbid and postmorbid considerations.
Pharmacokinetic as well as pharmacodynamic
variation occurs.
Evidence of genetic polymorphism of receptor
populations and signal transduction systems.
PREMORBID ISSUES
Diabetes
 Hypertension
 Hx of CHF
 Use of vasoactives
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PRELOAD
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Development of tachycardia in response
to inotropes often indicative of low
preload.
Absence of pressor response or active
deterioration in response to inotropes
may result from dynamic left ventricular
outflow tract obstruction (DLVOTO).
DLVOTO
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Anterior mitral valve leaflet impinges on
LVOT.
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Results in MR and/or obstruction.
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Classically found in HOCM.
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Common occurrence in setting of LVH and
under filling.
INOTROPY IN ENDOTHELIAL
INJURY
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Ischemia / reperfusion injury.
Massive endothelial apoptosis associated
with sepsis.
Loss of autoregulation.
Paradoxical responses.
Diminished catecholamine metabolism.
ALTERED KINETICS
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Significant metabolism of norepinephrine and
dopamine in the lung.
Dopamine most prone to variable kinetics
particularly with combined hepatic and renal
dysfunction.
Milrinone is renal excreted with markedly
prolonged half-life in renal failure and
unknown kinetics on CVVHD.
The number of receptor subtypes seems to
be creeping up with ever more complex
interactions.
RECEPTOR POPULATIONS
CHF associated with change in number
and type of receptors.
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Decreased numbers of 1 receptors
Increased expression of 3 receptors
Increased expression of 1 receptors
ALTERED G PROTEIN COUPLING
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Most vasoactive agents activate G protein
coupled receptors (GPCR).
Increased substitution of Gi subunit into
heterotrimer causing decreased responsiveness.
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Overexpression of Gi in sepsis.
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Stimulated by increased NO production.
PATHWAYS FOR RECEPTOR
DESENSITIZATION
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Phosphorylation by GPCR kinase and
subsequent internalization linked to
receptor activation.
Phosphorylation by serine / threonine
kinases not linked to receptor activation.
SECOND MESSENGER
GENERATION
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Phospholipase C
Adenyl cyclase
NOS
Guanylate cyclase
All subject to polymorphism and
multiple control systems
CORTISOL
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Increases transcription and expression of
adrenergic receptors.
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Required for synthesis of catecholamines.
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Reduces transcription of iNOS.
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True and relative cortisol deficiency seems
common in sepsis.
CATECHOLAMINES
NOREPINEPHRINE
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Potent 1 agonist equivalent to epinephrine.
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Potent 1 agonist.
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Lacks 2 agonism therefore unopposed
vasoconstriction.
Also has 2 activity which may limit
splanchnic blood flow.
EPINEPHRINE
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Potent 1 and 1 agonist.
Potent 2 agonist therefore increased
muscle blood flow.
Marked metabolic effects with major
increase in lactate production.
Demonstrated to promote GI ischemia.
DOPAMINE
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Direct 1 effects.
Indirect effects due to peripheral release
of norepinephrine.
Highly variable often exhibiting
significant 1 activity at low doses.
The triphasic response described in the
texts is fictional in clinical practice.
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Low dose dopamine causes dilation of
efferent and afferent renal arterioles and
significant increase in renal blood flow
without impact on glomerular pressure or
GFR in the normal kidney.
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In sepsis changes in renal blood flow due
to changes in perfusion pressure only.
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Impairs solute reabsorption proximally
and may promote diuresis.
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Profound effects on anterior pituitary
function.
PHENYLEPHRINE
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Pure 1 agonist
May be inappropriate alone in setting of
myocardial depression and ventricular
dilatation.
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Useful when arrhythmias aggravated by 
agonists.
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Some evidence that the absence of 2 activity
may preserve splanchnic blood flow.
VASOPRESSIN
VASOPRESSIN IN SHOCK
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Little role in blood pressure control normally.
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Vasodilatory actions in some tissue beds.
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Profound increase with onset of shock of all
kinds.
High levels maintained in cardiogenic shock but
drop quickly in sepsis to physiologic levels.
Cause of drop uncertain but some evidence of
depletion of neurohypophysis.
Low levels early in shock predictive of refractory
hypotension.
VASOPRESSIN
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Extreme sensitivity to small doses in sepsis.
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Usual dose range 0.01 - 0.04 Us / min.
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Consistently increases MAP and usually increases
U.O.
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Concern re effects on splanchnic blood flow but
little evidence of reduced flow in experimental
models or clinically.
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Superior to norepinephrine in most models.
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No hard outcome data as yet.
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Used as 2nd line agent to decrease norepi
dependence.
DOBUTAMINE
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Racemic mixture
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(+) enantiomer activates 1 and 2
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(-) enantiomer activates 1 receptors
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Usually behaves as pure inotrope but occasionally
exhibits significant peripheral effects.
Some evidence of microcirculatory recruitment
unrelated to systemic hemodynamics.
MILRINONE
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Inhibits PDE III increasing cAMP levels.
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Independent of  receptor.
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Potent inotrope and vasodilator.
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Less arrythmogenic than  agonists.
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May be used alone or in combination with other
inotropes.
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Often requires  agonists or vasopressin  to
control vasodilatation.
LEVOSIMENDAN
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Calcium sensitizing agent
Hemodynamic profile similar to milrinone
with significant peripheral dilation
Compares favorably with dobutamine in heart
failure (LIDO trial).
Favorable reports in sepsis.
? SUPRANORMAL DO2
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Patients who spontaneously achieve high levels
of DO2 have better outcomes.
Trials using therapies to achieve similar levels of
DO2 have not consistently demonstrated
improved outcomes.
Current approach not to target high DO2 in the
absence of lingering signs of tissue hypoxia.
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Demonstrated that early resuscitation of
the septic patient using SvO2 or ScvO2 as
an endpoint for adequacy of global oxygen
delivery produced a marked improvement
in outcome.
WHATS NEXT?
RESUSCITATION OF THE
MICROCIRCULATION
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Techniques now developed for visualizing and
investigating the microcirculation.
Some vasodilators lead to recruitment but
adverse effects on systemic hemodynamics.
rAPC may have its major beneficial effect by
preventing leukocyte adherence and obstruction.
N-acetylcysteine may have similar effects and
act as a microcirculatory dilator.
RESUSCITATION OF
MITOCHONDRIAL RESPIRATION
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Will enhanced antioxidant defenses be of
benefit?
Will enhanced substrate flow maintain
energetics?
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Will stimulation of mitochondrial activity with
leptin lead to earlier return of organ functions?
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Will we routinely be monitoring the electron
transport chain with NADH fluometry and NIR?
SUMMARY
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Classification
Common Pathways for Shock
Initial Management
Characterization
Mechanism of Inotropy
Catecholamines
What’s Next?